Grants and Contracts Details
Description
Nickel-containing compounds are human carcinogens. The mechanisms of their carcinogenic actions remain
to be investigated. Recent studies have indicated that reactive oxygen species (ROS) my play an important
role. We hypothesize that nickel induces generation of ROS, which activate nuclear transcription factors,
leading to cell transformation and tumorigenesis. Specific Aim 1 will detect and identify ROS generated in
human bronchial epithelial (BEAS-2B) cells exposed to nickel compounds and investigate the mechanism
involved. We hypothesize that nickel (Ni3S2 and NiCI2) can stimulate BEAS-2B cells to activate NADPH
oxidase via cdc42 and p47phox to produce superoxide radical, which is then converted to hydrogen peroxide
and hydroxyl radical. Specific Aim 2 will test the hypothesis that ROS are required for activation of NFAT and
NFkappaB in BEAS-2B cells and in vivo in response to nickel compounds. The role of ROS in nickel-induced
activation of NFAT and NFkappaB in BEAS-2B cells will be evaluated by co-transfection of NFkappaBluciferase
or NFAT-Iuciferase reporter plasm ids and specific ROS scavenger enzymes. For in vivo study,
BALB/c transgenic mice with alternation of antioxidant enzymes or NADPH oxidase (ROS generating
enzyme) will be employed. Specific Aim 3 will Investigate the role of ROS, NFAT and NFkappaB in nickelinduced
cell transformation and tumorigenesis. We hypothesize that ROS activate transcription factors and
cause cell transformation and tumorigenesis. We will use overexpression of DN-NFAT, DN-lkappaBalpha
and DN-IKKbeta to investigate the involvement of NFAT and NFkappaB in nickel-cell transformation and
induced tumorigenesis. The role of ROS will be investigated using specific antioxidant enzyme expressions
and NADPH oxidase alternation. We anticipate that nickel causes activation of NFAT and NFoB through
ROS reactions, leading to cell transformation and tumorigenesis. We attempt to link the cell transformation
and tumorigenesis with specific transcription factors and specific reactive oxygen species. The results
obtained from this proposal will elucidate the role of ROS and NFAT/NFkappaB signaling in Ni compoundsinduced
carcinogenesis. The long term goals are to provide a fundamental understanding concerning the
mechanism of carcinogenic actions of Ni; to fill a need for the mechanistic information of cancer risk
assessment for exposure; to propose methods for early detection; and to develop intervention and
Status | Finished |
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Effective start/end date | 3/1/08 → 2/28/15 |
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